Grant: Project Grant

Diabetic kidney disease is the leading cause of kidney failure in Canada. Although significant treatment advances have been made, many patients with diabetes still develop significant kidney injury, ultimately progressing to kidney failure. One of the main reasons why diabetic kidney disease still progresses is that scarring, a critical cause of kidney injury in diabetes, remains poorly understood and thus not well treated. Historically, researchers have focused on chemical triggers of scarring such as high blood sugar levels. As scarring develops, however, the kidney also progressively stiffens. We recently found that this kidney stiffening is an important mechanical trigger for further scarring. How cells respond to diabetes-induced chemical and mechanical stimuli to cause kidney scarring has so far remained a mystery. We and others have recently found that: (1) YAP and TAZ are two important proteins that respond to high sugar (chemical) and kidney stiffness (mechanical) injury stimuli, and (2) YAP and TAZ are important drivers of kidney scarring. In this proposal, we will test whether cells use YAP and TAZ as final common injury sensors to trigger kidney scarring in diabetes, and examine how YAP and TAZ use high sugar and kidney stiffness stimuli to activate scar production. These studies will provide important insights into how kidney scarring begins early in diabetes, and progresses at later stages. Early in diabetes, sugar levels are increased but the kidney is soft because it is not yet scarred. We hypothesize that YAP and TAZ are activated only by high blood sugar in this setting. Later, sugar levels remain increased, but because the kidney has now become scarred, it has stiffened. At this stage, YAP and TAZ are activated both by high sugar levels and the stiffened kidney. Most importantly, if successful, these studies will establish anti-YAP and TAZ treatments as a way to effectively treat both the early and late stages of diabetic kidney disease.